Age- and Sex-Related Characteristics of Tonic Gaba Currents in the Rat Substantia Nigra Pars Reticulata

Abstract

Previous studies have shown that the pharmacologic effects of GABAergic drugs and the postsynaptic phasic GABAAergic inhibitory responses in the anterior part of the rat substantia nigra pars reticulata (SNRA) are age- and sex-specific. Here, we investigate whether there are age- and sex-related differences in the expression of the δ GABAA receptor (GABAAR) subunit and GABAAR mediated tonic currents. We have used δ-specific immunochemistry and whole cell patch clamp to study GABAAR mediated tonic currents in the SNRA of male and female postnatal day (PN) PN5-9, PN11-16, and PN25-32 rats. We observed age-related decline, but no sex-specific changes, in bicuculline (BIM) sensitive GABAAR tonic current density, which correlated with the decline in δ subunit in the SNRA between PN15 and 30. Furthermore, we show that the GABAAR tonic currents can be modified by muscimol (GABAAR agonist; partial GABACR agonist), THIP (4,5,6,7-tetrahydroisoxazolo (5,4-c)pyridin-3-ol: α4β3δ GABAARs agonist and GABACR antagonist), and zolpidem (α1-subunit selective GABAAR agonist) in age-and sex-dependent manner specific for each drug. We propose that the emergence of the GABAAR-sensitive anticonvulsant effects of the rat SNRA during development may depend upon the developmental decline in tonic GABAergic inhibition of the activity of rat SNRA neurons, although other sex-specific factors are also involved.

Activity- and sleep-dependent regulation of tonic inhibition by Shisa7

“…We noticed that in young adult mice (6–8 weeks old), tonic inhibitory currents in hippocampal CA1 neurons were smaller than that in juvenile mice between 2 and 3 weeks old. A similar change of tonic inhibition during development has previously been reported ( Al-Muhtasib et al, 2018 ; Chudomel et al, 2015 ; Holter et al, 2010 ; Pandit et al, 2017 ). Our data indicate that the decrease of tonic inhibition in hippocampal CA1 neurons in WT young adult mice is due to a significant reduction of the component of α5-GABA A R-mediated tonic currents.…”

Allopregnanolone Decreases Evoked Dopamine Release Differently in Rats by Sex and Estrous Stage

“…Other studies confirm similar sex differences in allopregnanolone action; for example, females that received allopregnanolone were less sedated and recovered more rapidly from the neurosteroid effect than males at the same dose ( Irwin et al, 2015 ). Similarly, the α4β3δ GABA A receptor agonist THIP induced significantly greater tonic current in the substantia nigra pars reticulata neurons of young male rats than of females at the same age ( Chudomel et al, 2015 ). We can speculate that the sex variance on the inhibitory action of allopregnanolone could be explained, at least in part, by a greater expression of GABA A receptors in males compared to females ( Juptner and Hiemke, 1990 ).…”

Sex as a biological variable in the pathology and pharmacology of neurodegenerative and neurovascular diseases

“…Unfortunately, it took several years and many reports of adverse events before dosing recommendations were changed in 2013 to a lower recommended dose in women. Recent studies using immunochemistry and whole cell patch clamp recording of tonic currents have shown that zolpidem modulated the activity of its target receptor in an age‐ and sex‐dependent manner (Chudomel, Hasson, Bojar, Moshe, & Galanopoulou, ). Zolpidem serves as an example where the initially neglected sex‐dependent response to a potent pharmacological agent triggered a regulatory change by the FDA.…”